The central aim of this CCNE project is to develop nanotechnologies for targeted combination pharmacotherapy using existing compounds with suboptimal pharmaceutical properties. The genomic revolution has resulted in the identification of approximately ~320 molecular targets and attempts to therapeutically utilize many of these have faced considerable development challenges (1, 2). More recently, advances in systems biology have aided in identifying synergistic pathways among these newly identified targets that may be concurrently utilized for more effective treatment of cancers. The development of nanotechnologies for effective delivery of multiple drugs or drug candidates in a temporally regulated manner to cancer cells can potentially overcome the development challenges faced to date, and result in harnessing the maximal benefits of cancer genomics and systems biology (3, 4). Our early work supported by the MIT-Harvard CCNE focused on engineering targeted nanoparticles for delivery of a single chemotherapeutic agent (docetaxel) for prostate cancer (PCa) therapy. Using a combinatorial process for engineering libraries of targeted nanoparticles by selfassembly, which is reproducible, we screened and Identified particles with optimal biophysicochemical properties. Particles with optimal properties are now in clinical development and approaching an IND in 2010./n the context of this proposal we hypothesize that 1) by engineering and blending distinct drugfunctionalized and ligand-functionalized polymers, with or without encapsulation of additional free drug molecules, we will be able to reproducibly engineer and characterize nanoparticles capable of delivering 2 or more drugs; and 2) by targeting these drug loaded nanoparticles to cancer cells we can achieve synergistic drug effects which may translate to better efficacy and tolerability making them suitable for potential clinical development. Herein we propose to develop technologies for co-delivery of up to 3 distinct anticancer agents for targeted combination chemotherapy. As a model cancer, building on our previous efforts, we propose to develop long circulating drug-conjugated targeted nanoparticles for differential uptake by PCa cells. We will aim to develop targeted nanoparticles with up to 3 distinct anticancer agents and place one candidate formulation on a development path toward an IND submission in 2014, setting the stage for clinical validation of our TempoSpatially-controlled Combination Chemotherapy (TSCC) platform in patients with hormone refractory prostate cancer (HRPC).